The burden of prostate cancer (PC) is tremendous, accounting for approximately 220,000 new cases and 32,050 deaths in the US in 2010 alone. In many patients, PC exhibits an indolent biologic phenotype with a prolonged course-in some cases, extending over 15 years following the initial diagnosis. Thus, the opportunity to intervene early and alter the course and progression of this disease is readily available. Androgen receptor (AR) signaling plays a crucial role in the normal growth of the prostate as well as in PC initiation and progression. Thus, modulation of AR activation and expression represents a logical target for PC prevention and treatment. Recent clinical studies demonstrate that pharmacological inhibition of AR signaling reduces PC risk. However, AR- mediated functions are not completely abrogated by existing hormone therapies. Therapeutic failure is often accompanied by molecular alterations of the AR, including AR overexpression as well as expression of constitutively active AR variants. Our experiments demonstrate for the first time that piperlongumine (PL), a naturally occurring derivative of black pepper, induces rapid AR degradation through a proteasome-mediated pathway which coincides with inhibition of AR transcriptional activity and reduced proliferation of hormone- dependent LNCaP PC cells. We hypothesize that PL can inhibit prostate carcinogenesis at both initiation and advanced disease stages via depletion of the AR either alone or in combination with current androgen deprivation therapeutic regimens. Indeed, hormone ablation and depletion of AR may have a complementary effect on the inhibition of prostate carcinogenesis. The overall objective of this application is to explore the mechanisms of PL- mediated AR depletion and to test PL efficacy for the primary and secondary PC prevention. To test our hypothesis and to evaluate the therapeutic potential of PL for prostate cancer prevention, we propose the following Specific Aims: Aim 1: To investigate the mechanism of PL-mediated AR depletion in prostate cancer cells. Specific Aim 2: To investigate the effect of PL on primary and secondary PC prevention using in vivo models. PUBLIC HEALTH RELEVANCE: Androgen receptor signaling plays a crucial role in the normal growth of prostatic tissue as well as in prostate cancer initiation and progression. Our work demonstrates for the first time that piperlongumine, a naturally occurring derivative of black pepper, induces rapid androgen receptor degradation in prostate cancer cells through a proteasome-mediated pathway which coincides with reduced functional activity of androgen receptor signaling and decreased cell proliferation. The overall objective of this application is t explore the mechanisms of piperlongumine-mediated androgen receptor depletion and to test piperlongumine efficacy for the primary and secondary prostate cancer prevention.